Analgesic and neuroprotective effects of Baimai Ointment on diabetic peripheral neuropathy.

ETHNOPHARMACOLOGY RELEVANCE: Baimai (BM) ointment, a traditional Tibetan medicine, has been widely used to treat "white vein" disease, paralysis, hemiplegia and claudication caused by trauma, because of its great effects on muscle stretching and collateral activation. As one of the most terrible complications in diabetes patients, diabetes peripheral neuropathy (DPN) is mainly manifested as abnormal pain or numbness in extremities. However, whether BM ointment is a potential drug for DPN treatment is unclear. AIMS OF THE STUDY: The aim of this study was to investigate the therapeutic effects of BM on DPN in a high-fat diet/low-dose of streptozotocin induced type 2 diabetes rat model and explore underlying mechanisms. METHODS: The chemical components of BM were determined by high performance liquid chromatography (HPLC), and the possible targets and related pathways candidates involved in the effects of BM on DPN were predicted using network pharmacology methods. Next, the effects of different doses (1.5, 3.0 and 6.0 g/kg) of BM on physiological changes, pain behaviors, motor nerve conduction velocity (MNCV) in DPN rats were assessed and compared with placebo- and mecobalamine (Meco)-treated DPN controls. Then, the effects of BM on the expression of pain associated genes as well as the phosphorylation of PI3K/AKT and MAPKs pathways in DRG of DPN rats were examined. RESULTS: Through HPLC analysis, curcumin was identified as one of the primary contents of BM. The information from network pharmacology indicated a series of target candidates for BM including IL6, IL10, TNF, CCL2, CXCL12, EGF, VEGFA, BDNF, TGFß1 and TNF, as well as PI3K-AKT and MAPK signaling pathways. Topical treatment of BM significantly improved the hypersensitivity of mechanical and thermal pain, MNCV and the morphological changes and demyelination of sciatic nerve fibers, without affecting the body weight, serum metabolism or blood glucose. The up-regulated levels of neuropeptides Cgrp, Sst, Sp and chemokines Ccl2 and Ccl3 along with the abnormal expression of p-P38, p-ERK and p-AKT in the DRG of DPN rats were alleviated by BM application. CONCLUSION: BM ointment has great activities in relieving pain hypersensitivity, neuroprotecting peripheral nerves damage caused by DPN, which may be related to the inhibition of related neuropeptide (Cgrp, Sst, Sp) and chemokine (Ccl2, Ccl3) expression and the regulation of PI3K/AKT and MAPKs signaling pathways in DRG.

Fluconazole plus flucytosine is a good alternative therapy for non-HIV and non-transplant-associated cryptococcal meningitis: A retrospective cohort study.

Cryptococcal meningitis (CM) carries a high risk of mortality with increasing incidences in immune competent hosts. Current treatments are not well tolerated, and evaluation of other treatments is needed. Fluconazole and 5-flucytosine in treating immune competent hosts have not been characterised. To evaluate the efficacy of fluconazole and 5-flucytosine in treating non-HIV- and non-transplant-associated CM. We performed a retrospective cohort study of the outcomes in immune competent patients with CM treated with fluconazole and 5-flucytosine or deoxycholate-amphotericin B and 5-flucytosine. The primary outcome was treatment response evaluated at the 12th week after initiation of antifungal therapy. A total of 43 and 47 patients received amphotericin B deoxycholate and 5-flucytosine or fluconazole and 5-flucytosine, respectively. A total of 38 (88.4%) patients cannot tolerate recommended doses of amphotericin B deoxycholate and 5-flucytosine (patients needed dose reduction during the treatment). Patients given fluconazole and 5-flucytosine had higher baseline cryptococcal burdens (median 3632 versus 900 cryptococci/mL, P = 0.008). No significant differences were seen in cryptococcus clearance (74.4% vs 70.2%, P = 0.814), treatment time (39 days, 20-69 days vs 21 days, 7-63 days, P = 0.107) and successful response (including complete and partial responses) rates (69.7% vs 72.3%, P = 0.820). Fluconazole and 5-flucytosine treatment had lower total adverse events (19.1% vs 90.7%, P < 0.001). Fluconazole and 5-flucytosine had relatively high efficacy with few adverse events in treating CM. Fluconazole and 5-flucytosine therapy is promising in patients that do not tolerate or are not suited for amphotericin B deoxycholate treatment.

Genome-wide association study of phosphorus-deficiency-tolerance traits in Aegilops tauschii.

KEY MESSAGE: Using GWAS, 13 significant SNPs distributed on six of the seven Aegilops tauschii chromosomes (all but 5D) were identified, and several candidate P-deficiency-responsive genes were proposed from searches of public databases. Aegilops tauschii, the wheat (Triticum aestivum) D-genome progenitor, possesses numerous genes for stress resistance, including genes for tolerance of phosphorus (P) deficiency. Investigation of the genetic architecture of A. tauschii will help in developing P-deficiency-tolerant varieties of wheat. We evaluated nine traits in a population of 380 A. tauschii specimens under conditions with and without P application, and we performed genome-wide association studies for these traits using single nucleotide polymorphism (SNP) chips containing 7185 markers. Using a general linear model, we identified 119 SNPs that were significantly associated with all nine traits, and a mixed linear model revealed 18 SNPs associated with all traits. Both models detected 13 significant markers distributed on six of the seven A. tauschii chromosomes (all but 5D). Searches of public databases revealed several candidate/flanking genes related to P-deficiency tolerance. These genes were grouped in five categories by the types of proteins they encoded: defense response proteins, enzymes, promoters and transcription factors, storage proteins, or proteins triggered by P deficiency. The identified SNPs and genes contain essential information for cloning genes related to P-deficiency tolerance in A. tauschii and wheat, and they provide a foundation for breeding P-deficiency tolerant wheat cultivars.